Effects of some novel D-myo-inositol-phosphate derivatives on binding and sympathetic transmission

Xiang Ying Sun, Lars Edvinsson, Heahyun Yoo, Claes Wahlestedt, Thomas Hedner

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The vascular effects of myo-inositol and a series of n-myo-inositol phosphate derivatives: D-myo inositol-1-monophosphate (Ins[1]P1), D-myo- inositol-2-monophosphate (Ins[2]P1), D-myo-inositol-1, 2-biphosphate (Ins[1,2]P2), D-myo-inositol-1,2,6-trisphosphate (Ins[1,2,6]P3, α- trinositol; PP56), D-myoinositol-1,2,5,6-tetraphosphate (Ins[1,2,5,6]P4), and D-myo-inositol-1,2,3,4,5,6-hexa-phosphate (InsP6, phytic acid) were studied in binding assays in rat heart membranes, in vitro in isolated guinea pig basilar artery, and in vivo in pithed rats. In binding assays in rat heart membranes, Ins[1,2,6]P3, Ins[1,2,5,6]P4, and InsP6, displaced the binding of [3H]α-trinositol [3H][1,2,6]P3). In the isolated guinea pig basilar artery, Ins[1,2]P2 and Ins[1,2,6]P3 inhibited the contractile effects of exogenous neuropeptide Y (NPY) in the concentration range of 10 - 8-10 -6 M. In pithed Sprague-Dawley rats, Ins[1,2,6]P3 inhibited the NPY- induced pressor response in the dose range [2 mg/kg (3.8 μmol/kg) combined with an infusion of 20 mg/kg/h (38 μmol/kg/h) for 30 min] in which no inhibitory effects on the pressor responses were elicited by preganglionic nerve stimulation (PNS) or a bolus injection of phenylephrine (Phe). Ins[1,2]P2 had only slight NPY inhibitory effects in vivo. We conclude that selected inositol derivatives may inhibit the vasopressor effects to NPY in vitro and in vivo. In particular, Ins[1,2,6]P3, which most readily inhibited the NPY-induced pressor response in vivo, may represent a new class of synthetic nonpeptide drugs, which may inhibit the vascular effects of NPY without binding to the NPY receptor itself.

Original languageEnglish (US)
Pages (from-to)696-704
Number of pages9
JournalJournal of Cardiovascular Pharmacology
Volume25
Issue number5
DOIs
StatePublished - May 1995

Keywords

  • Cardiac membranes
  • Guinea pig basilar artery
  • Inositol 1,2,6- trisphosphate (α-trinositol)
  • Pithed rat
  • Structure activity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology

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